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Prevention and treatment of dengue virus infection

Authors: Stephen J Thomas, MD, Alan L Rothman, MD, Anon Srikiatkhachorn, MD, Siripen Kalayanarooj, MD
Section Editor: Martin S Hirsch, MD
Deputy Editor: Elinor L Baron, MD, DTMH

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jan 2017. | This topic last updated: Nov 02, 2016.

INTRODUCTION Dengue is a febrile illness caused by a flavivirus transmitted by the bite of an Aedes aegypti mosquito. There are four dengue virus types (DENV-1,
DENV-2, DENV-3, and DENV-4), all of which are capable of inducing severe disease (dengue hemorrhagic fever [DHF]/dengue shock syndrome [DSS]). Dengue is
endemic in more than 100 countries in tropical and subtropical regions and causes an estimated 390 million infections annually worldwide, of which 96 million are
clinically apparent [1].

The likelihood for development of severe dengue is highest among individuals who develop a second dengue infection caused by a different virus type from the first
infection (known as secondary or heterotypic infection) [2]. Thus, severe disease occurs primarily among individuals in areas where multiple serotypes circulate
simultaneously. Infection with dengue virus provides long-term protection against the particular serotype that caused the disease, supporting the feasibility of developing
an effective vaccine. However, infection provides only short-lived immunity to the other three dengue virus serotypes.

There are numerous documents providing guidance on the optimal approaches to managing dengue [3-6]. Data from well-designed randomized controlled trials are
limited. The guidance in this document largely agrees with published guidelines and is also based on the contributors' clinical experience in management of complex
dengue infections.

Measures to prevent dengue infection and supportive treatment for dengue virus infection will be reviewed here. The epidemiology, clinical manifestations, and
diagnosis of infection are discussed separately. (See "Epidemiology of dengue virus infections" and "Clinical manifestations and diagnosis of dengue virus infection".)

PREVENTION Dengue virus transmission occurs when susceptible hosts, dengue viruses, and mosquitoes capable of transmission are co-located in space and
time. Infection risk exists for anyone living in or traveling in a dengue-endemic region, especially in tropical Asia, Central and South America, and the Caribbean. In
most of these regions, dengue virus transmission occurs year-round. However, the greatest risk of infection tends to be seasonal or during a recognized outbreak.

Endemic areas Approaches for the prevention of dengue infection and disease in endemic areas include Aedes mosquito control and vaccine development.

Mosquito control Mosquito control is effective but is difficult to sustain. Approaches to mosquito control for prevention of dengue infection include:

Reducing breeding sites Community-based education to reduce breeding sites that accumulate standing water (such as discarded tires and other containers)
have shown some promise [7,8].

Larva control Seeding water vessels with copepods that feed on mosquito larvae was successful in eliminating A. aegypti and dengue transmission in one study
including 32 rural communities in Vietnam [9], although this strategy is difficult to apply in urban areas [10].

Use of insecticide Distribution of insecticide-treated curtains was successful in reducing populations of A. aegypti mosquitoes for up to 18 months in several
studies [11,12] and was associated with reduced human and mosquito infections with dengue virus in one region [12], although use of the curtains declined with
time. Insecticide spraying in response to dengue outbreaks is not highly effective since A. aegypti mosquitoes frequently breed inside houses [7,13].

Endosymbiotic control A novel strategy consists of releasing mosquitoes infected with the intracellular endosymbiotic bacterium Wolbachia [14,15]. Such
mosquitoes could reduce dengue virus transmission via several mechanisms, including reducing mosquito lifespan and inhibiting viral replication; these effects
could be propagated into later generations of mosquitoes via ongoing transmission of Wolbachia.

Programs in the 1940s through 1970s targeting the A. aegypti mosquito via aggressive surveillance and insecticide use for elimination of urban yellow fever in the
Americas were successful at reducing transmission of yellow fever as well as the dengue viruses [7]. Lack of funding and attention for these programs led to
reemergence of A. aegypti and corresponding reemergence of dengue.

Issues related to mosquito vector control are discussed further separately. (See "Malaria in endemic areas: Epidemiology, prevention, and control", section on 'Mosquito
control'.)

Vaccination Infection with one dengue virus type provides long-term protection against reinfection with that same type, supporting the feasibility of an effective
dengue vaccine. Following infection with one type, there is short-lived immunity and protection against disease caused by the other three dengue virus types [16]. In
view of the association between previous exposure to dengue viruses and severe disease and the recognition that all four virus types are capable of causing severe
disease, ideally any candidate vaccine should produce protective immunity against all four serotypes (tetravalent immunity). Since waning immunity might also increase
the risk for severe disease in vaccine recipients, vaccine-induced protective immunity should also be long lived [17].

A number of dengue vaccine candidates are in development [18,19]. One vaccine, CYD-TDV (Dengvaxia), has been licensed in a few endemic countries in Latin
America and Southeast Asia but not in the United States [20]. CYD-TDV is a formulation of four chimeric yellow fever 17D-dengue vaccine viruses, where the
premembrane and envelope proteins from each of the four dengue virus types replaces the same proteins in a yellow fever 17D backbone virus [21]. The basis for
licensure was two large phase III randomized controlled trials of CYD-TDV; results were reported in 2014 to 2015 [22,23]. One trial was conducted in five countries in
the Asia-Pacific region and enrolled children aged 2 to 14 years [22]; the other trial was conducted in five countries in Latin America and the Caribbean and enrolled
children aged 9 to 16 years [23]. The age groups were chosen based on likely target populations for vaccination and epidemiologic data of clinical attack rates.

In both trials, the CYD-TDV vaccine was administered in three doses at months 0, 6, and 12. Results from the two trials were comparable; in the primary per-protocol
analysis, vaccine efficacy was 57 and 61 percent against virologically confirmed dengue of any severity caused by any dengue virus type that occurred between 28
days and 13 months after the third vaccine dose. Vaccine efficacy was higher against dengue hemorrhagic fever or dengue infection requiring hospitalization (80 to 95
percent). Vaccine efficacy varied by serotype and was significantly higher for DENV-3 and DENV-4 (approximately 75 percent) than DENV-1 (50 percent) and DENV-2
(35 to 42 percent). Vaccine efficacy was lower (34 to 36 percent) in children 2 to 5 years of age and in children who did not have detectable dengue-neutralizing

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antibodies prior to vaccination. The safety profile was considered good, and there was no indication of more severe dengue disease in breakthrough cases in vaccine
recipients that occurred over the 25 months of active case surveillance.

Follow-up analyses of these vaccine trials have included the following:

An interim analysis published in 2015 noted that the vaccine was associated with an elevated relative risk for dengue infection requiring hospitalization during the
third year of the trial (between one and two years after the last dose of the vaccine) among children younger than nine years and particularly in children two to five
years of age [24]. It is unclear whether the increased risk will be sustained.

In an analysis including 3736 study participants, 443 had asymptomatic dengue infection (67 had virologically confirmed asymptomatic infection and 376 had
serologically confirmed infection) [25]. Vaccine efficacy against asymptomatic dengue infection was 33 percent overall (38 among recipients 9 years of age and 9
percent among recipients 2 to 9 years of age). Based on these data, it is feasible the vaccine may yield a public health benefit, though the durability of vaccine
impact and level of herd immunity required to affect dengue transmission are both unknown.

We are in agreement with the World Health Organization Strategic Advisory Group of Experts, which recommended that CYD-TDV be introduced only in geographic
settings with high dengue endemicity (defined as seroprevalence 70 percent in the age group targeted for vaccination or other suitable epidemiologic markers). The
vaccine should not be used in areas where seroprevalence is <50 percent [26].

Travelers The primary approach to prevention of dengue virus infections in travelers consists of avoiding exposure to infected A. aegypti mosquitoes, which
predominantly live in urban areas (in and around houses) and are most active during the daytime as well as at twilight [13]. Remaining in well-screened or air-
conditioned buildings during the day can reduce the risk of exposure. When outside during the day, individuals should wear clothing that reduces the amount of exposed
skin and should use an effective mosquito repellent, such as N,N-diethyl-metatoluamide (DEET). (See "Prevention of arthropod and insect bites: Repellents and other
measures".)

Most travelers from nonendemic countries are at exceedingly low risk for severe dengue in the absence of prior dengue virus exposure; potential exceptions include
frequent international travelers, expatriates, frequently deploying military personnel, and immigrants from endemic areas returning to their countries of origin.

People with history of dengue infection need not avoid subsequent travel to dengue-endemic regions. Severe dengue occurs in a small number of secondary infections
(2 to 4 percent), so the risk of severe dengue in travelers is very low.

TREATMENT APPROACH There is no direct antiviral therapy available against the dengue viruses. Management is supportive, which largely consists of maintaining
adequate intravascular volume.

Treatment guidelines have been published by the World Health Organization (WHO; 2009) and the WHO South-East Asia Regional Office (SEARO; 2011); there are
variations between these guidelines [27,28]. These are discussed in the following sections, which follow the framework of the revised dengue case classification. Where
relevant, significant differences in the recommendations are noted in the discussion below. (See "Clinical manifestations and diagnosis of dengue virus infection".)

Thus far, there has been no prospective validation of the approaches summarized in the WHO guidelines. The areas of greatest uncertainty are the sensitivity and
specificity of the criteria used for hospitalization and for initiation of fluid therapy. Some alternative clinical approaches that have been successful in endemic areas are
discussed below. (See 'Alternative management approaches' below.)

A definitive laboratory diagnosis of dengue is often not available at the point of care; therefore, it is also important to consider other treatable diagnoses. (See "Clinical
manifestations and diagnosis of dengue virus infection".)

Phases of infection and clinical assessment Dengue has three phases: febrile, critical, and convalescent/recovery [27,29]. The febrile phase is characterized by a
sudden high-grade fever and dehydration typically lasting two to seven days. The critical phase is characterized by plasma leakage, bleeding, shock, and organ
impairment; it usually starts around the time of defervescence (typically days 3 to 7 of infection) and lasts for 24 to 48 hours. Dengue hemorrhagic fever (DHF) and
dengue shock syndrome (DSS) include all three stages, while dengue fever does not include the critical phase (table 1). Criteria for DHF include fever,
thrombocytopenia, bleeding, and plasma leakage into serosal cavities. Loss of intravascular volume from plasma leakage and/or bleeding may lead to shock (dengue
shock syndrome).

Patients with suspected dengue should be assessed carefully and directed to the appropriate care setting. Early recognition of progression to severe disease and
patients at increased risk for severe disease is essential, with prompt initiation of more aggressive therapy when necessary.

The 2009 WHO classification for dengue severity includes three categories [27]:

Dengue infection without warning signs A presumptive diagnosis of dengue infection may be made in the setting of residence in or travel to an endemic area, plus
fever and two of the following:

Nausea/vomiting
Rash
Headache, eye pain, muscle ache, or joint pain
Leukopenia
Positive tourniquet test

Dengue with warning signs of severe infection This category includes dengue infection as defined above, in addition to any of the following warning signs:

Abdominal pain or tenderness


Persistent vomiting
Clinical fluid accumulation (ascites, pleural effusion)
Mucosal bleeding
Lethargy or restlessness
Hepatomegaly >2 cm
Increase in hematocrit concurrent with rapid decrease in platelet count

Severe dengue infection This category includes dengue infection with at least one of the following criteria:

Severe plasma leakage leading to:

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- Shock (dengue shock syndrome)
- Fluid accumulation with respiratory distress

Severe bleeding (as evaluated by clinician)

Severe organ involvement:

- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 1000 units/L


- Impaired consciousness
- Organ failure (heart or other organs)

Outpatient management is appropriate for patients with presumptive diagnosis of dengue infection in the absence of warning signs or coexisting conditions (pregnancy,
infancy, old age, diabetes, renal failure, underlying hemolytic disease, obesity, or poor social situation); such patients should be able to tolerate oral fluids, urinate at
least once every six hours, and have near normal blood counts [27].

Inpatient management is warranted for patients with dengue and warning signs of severe infection, severe dengue infection, or dengue infection with coexisting
conditions (algorithm 1). Dramatic plasma leakage can develop suddenly; early identification of patients at increased risk for shock and other complications is critical.
The period of maximum risk for shock is between the third and seventh day of illness, which typically coincides with resolution of fever. In general, plasma leakage first
becomes evident between 24 hours before and 24 hours after defervescence.

Laboratory abnormalities include derangements in blood counts and liver function tests. An elevated hematocrit is an indication that plasma leakage has already
occurred and that fluid repletion is required. Confounding factors should be considered when interpreting the hematocrit, including dehydration (associated with
increased hematocrit) and hemorrhage (associated with reduced hematocrit). Marked thrombocytopenia (100,000/mm3) is a criteria for DHF and usually precedes
overt plasma leakage. Mild elevations in serum transaminases are common in the setting of dengue infection; transaminase levels are significantly elevated in patients
with DHF. In addition, elevated AST levels are common relatively early in the course of illness; in one Thai study, a normal AST level was a strong negative predictor of
DHF (negative predictive value 0.96) [30]. (See "Clinical manifestations and diagnosis of dengue virus infection", section on 'Dengue hemorrhagic fever'.)

Outpatient management Outpatient management is appropriate for patients with presumptive diagnosis of dengue in the absence of warning signs or coexisting
conditions as summarized in the preceding section. Most patients with dengue do not develop severe illness and can be safely managed in the outpatient setting. (See
'Phases of infection and clinical assessment' above.)

Patients should be instructed regarding the warning signs of severe dengue infection and the critical phase that follows defervescence (which lasts for 24 to 48 hours;
during this period, patients may deteriorate rapidly). During the febrile phase (lasting two to seven days) and the subsequent critical phase (lasting one to two days),
serial blood counts should be followed (particularly to evaluate for increase in hematocrit concurrent with rapid decrease in platelet count), the patient should be
evaluated daily from the third day of illness through the end of the critical phase for signs of dehydration and other warning signs of severe dengue.

Fever may be controlled with acetaminophen; nonsteroidal anti-inflammatory drugs and aspirin-based products should not be used out of concern for their effect on
platelet function and the potential increased risk for bleeding. (See 'Management of fever' below.)

Patients should be instructed to take plenty of fluids and watch for signs of dehydration (decrease in urination, few or no tears, dry mouth or lips, sunken eyes,
listlessness or confusion, cold or clammy extremities, sunken fontanel in an infant); these findings warrant prompt clinical evaluation. As fever declines (three to eight
days after onset of symptoms), patients should be instructed to seek prompt attention for any of the following: severe abdominal pain, persistent vomiting, skin rash,
bleeding from nose or gums, vomiting blood, dark stools, drowsiness or irritability, pale or cool skin, and difficulty breathing.

Patients in endemic areas should take measures to prevent dengue virus transmission. If possible, all mosquitoes in the house should be eliminated, screens should be
placed on windows and doors to prevent mosquitoes from coming into the house, and containers holding standing water should be emptied. To avoid infecting
mosquitoes (which can in turn infect others in the household), if possible the patient should sleep under a bed net and use insect repellant while ill.

Inpatient management Inpatient management is warranted for patients with dengue and warning signs of severe infection, severe dengue infection, or dengue
infection with coexisting conditions (pregnancy, infancy, diabetes, poor social situation, old age, or renal failure). (See 'Phases of infection and clinical assessment'
above.)

Patients warranting inpatient management should be assessed for signs of impending shock (table 1). In the absence of shock, patients may be managed as
summarized in the algorithm (algorithm 1) [3]. Most patients who present for medical attention before profound shock develops and who receive appropriate fluid
therapy recover quickly.

In setting of shock (normal systolic pressure but rising diastolic pressure with narrowing pulse pressure), patients may be managed as summarized in the algorithm
(algorithm 2). In the setting of profound or prolonged shock (hypotension, narrow pulse pressure [systolic minus diastolic pressure 20 mmHg]), patients may be
managed as summarized in the algorithm (algorithm 3).

Management of fever Fever and myalgias should be managed with acetaminophen (maximum 60 mg/kg/day in children; 4 g/day in adults). Aspirin or nonsteroidal
anti-inflammatory agents should be avoided because of the risk of bleeding complications and because of the potential risk of Reye's syndrome in children. (See "Acute
toxic-metabolic encephalopathy in children", section on 'Reye syndrome'.)

Management of plasma leakage Plasma leakage should be managed with intravascular volume repletion to prevent or reverse hypovolemic shock (algorithm 1). In
mild cases, particularly when medical attention is received early, oral rehydration may be sufficient. Administration of intravenous fluid is warranted in patients with
established intravascular volume loss. Blood transfusion is appropriate in patients with significant bleeding or low hematocrit and failure improve with fluid resuscitation.
Subsequent hematocrit measurements must be interpreted with caution since it is critical to assess the adequacy of both blood and fluid repletion; in complex cases, it
can be challenging to distinguish whether a decrease in hematocrit reflects volume repletion or blood loss.

Treatment of shock Protocols for intravenous fluid therapy have been developed by the World Health Organization (WHO) [27,28]; these are summarized in the
algorithms (algorithm 2 and algorithm 3). There are a number of acceptable approaches to management of shock associated with dengue, and there are no clinical trial
data favoring one approach over the other. The process of frequent clinical assessment is critical to ensure judicious fluid resuscitation and detection of hemorrhage if
present.

Initial fluid resuscitation with crystalloid is appropriate; there is no clinical advantage of colloid over crystalloid [31-33]. In one randomized trial including 512 Vietnamese
children with moderate dengue shock syndrome, outcomes were similar with Ringer's lactate, 6% dextran 70, and 6% hydroxyethyl starch [33], establishing that

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Ringer's lactate is a safe, effective, and inexpensive crystalloid solution for initial resuscitation of patients with moderate shock. In patients with severe shock, dextran
and starch performed similarly, although dextran was associated with more hypersensitivity reactions.

Intravenous colloid solution is warranted for patients with intractable shock resistant to crystalloid resuscitation; in such cases, we favor 10% dextran 40 in normal
saline. Patients with persistent hypoperfusion and falling hematocrit require blood transfusion and should be evaluated for occult or overt bleeding. Other possible
complications (such as acidosis, hypoglycemia, and hypocalcemia) should be investigated and corrected as needed. (See "Treatment of severe hypovolemia or
hypovolemic shock in adults" and "Hypovolemic shock in children: Initial evaluation and management".)

Once hemodynamic stability has been restored, intravenous fluids should be continued with gradual reduction of the infusion rate over the next 24 to 48 hours. There
have been no controlled comparisons of infusion regimens; we typically reduce the infusion rate as follows: 10 mL/kg over the first hour, then 7 mL/kg/hour for 1 to 2
hours, 5 mL/kg/hour for 4 to 6 hours, and 3 mL/kg/hour for 6 to 12 hours. This gradual reduction is intended to minimize the risk of recurrent shock and volume
overload. The patient's clinical status (including vital signs, urine output, and hematocrit) should be evaluated prior to each infusion rate adjustment.

Close clinical observation is essential even after restoration of normovolemia; the 24 hours following initial resuscitation is a period of increased vascular permeability,
and patients can develop recurrent shock during this period. Fluid lost into potential spaces (pleura, peritoneum) during the period of plasma leakage is reabsorbed
rapidly. Therefore, intravenous fluid supplementation should be discontinued following the period of increased vascular permeability; excessive fluid administration after
this point can precipitate hypervolemia and pulmonary edema.

In the absence of complications from prolonged hypotension, most patients with severe dengue infection recover within a few days [34]. Discharge from the hospital is
appropriate when patients have been afebrile for at least 24 hours or have passed two days after an episode of shock, are clinically well, and have normal appetite,
urine output, and hematocrit.

Management of bleeding Gastrointestinal bleeding, epistaxis, or menorrhagia may be severe enough to warrant blood transfusion. Significant internal bleeding
should be suspected in patients with signs of intravascular hypovolemia without elevation of hematocrit. In these circumstances, blood transfusion should be performed
(5 mL/kg of packed red blood cells or 10 mL/kg whole blood in children; 1 unit of packed red blood cells or whole blood in adults). The clinical response and
posttransfusion hematocrit should be monitored. (See "Approach to acute upper gastrointestinal bleeding in adults" and "Approach to acute lower gastrointestinal
bleeding in adults".)

Factors that contribute to bleeding include thrombocytopenia due to decreased platelet survival [35] and, in severe cases, prolonged prothrombin time (international
normalized ratio >1.3) and frank disseminated intravascular coagulation due to liver failure. Platelet transfusion has not been shown to be effective at preventing or
controlling hemorrhage but may be warranted in patients with severe thrombocytopenia (<10,000/mm3) and active bleeding. In general, there is no role for prophylactic
platelet transfusion in patients with severe thrombocytopenia in the absence of active bleeding [27,36-38]. Administration of intravenous vitamin K is warranted for
patients with severe liver dysfunction or prolonged prothrombin time [28].

ALTERNATIVE MANAGEMENT APPROACHES Treatment guidelines have been published by the World Health Organization (WHO; 2009) and the WHO South-
East Asia Regional Office (SEARO; 2011); there are variations between these guidelines [27,28].

Clinical practice is informed by the above guidelines as well as clinical experiences with managing dengue in different populations. There have been no rigorous trials
comparing clinical approaches or establishing endpoints (clinical or laboratory based) for management of severe disease.

The following indications for inpatient admission have been used at the Queen Sirikit National Institute for Child Health in Bangkok, Thailand, since 1999 [39,40]:

Shock or impending shock


Leukopenia (white blood cell count 5000 cells/mm3 or lower) and/or thrombocytopenia (platelet count 100,000 cells/mm3 or lower), especially in high-risk patients
(infants, older adults, pregnancy, patients with comorbidities)
Clinical deterioration or lack of clinical improvement with defervescence
Significant bleeding (epistaxis, hematemesis, melena, hematuria, or excessive menstrual bleeding)
Altered consciousness
Difficulty with follow-up
Family concern/anxiety

Published experience with systematic application of more restrictive criteria for admission of patients with suspected dengue is limited. This includes an uncontrolled
study in Malaysia conducted over a two-month period [41] and case series from Singapore describing the clinical experience with institutional admissions guidelines
[42]. The major criteria for hospitalization in those sites included:

Blood pressure <90/60 mmHg


Hematocrit >50 percent
Platelet count <50,000/mm3
Evidence of bleeding other than petechiae

Additional criteria for hospitalization in the Singapore study included pulse 100 beats/minute, severe abdominal pain, persistent vomiting, and older adult patients with
comorbidities. Both groups reported successful management with no complications resulting from outpatient care; however, the studies involved only adults, and the
number of cases of severe dengue/dengue hemorrhagic fever (DHF) was relatively small (28 in Malaysia and 148 in Singapore). In case series in Thailand and
Singapore, the WHO criteria for dengue with warning signs of severe infection would have led to an excess of hospitalizations and/or treatment relative to local clinical
practice [42,43].

Routine laboratory testing is not readily available in many resource-limited settings where dengue is endemic. One study including 1250 children aged 2 months to 10
years in southern Vietnam evaluated whether an assessment tool using only clinical signs could appropriately guide management of acute illness [44]. The assessment
tool was derived from the WHO/United Nations Children's Emergency Fund (UNICEF) "Integrated Management of Childhood Illness" algorithm designed for use in
Africa and was modified to include common signs and symptoms of DHF. The 20 children who presented with dengue shock syndrome were correctly identified as
requiring urgent hospitalization, although classification of less severe DHF was imperfect, and reevaluation within one to two days was needed to detect children who
developed shock.

Several studies have applied decision-tree analysis to develop algorithms for early management of patients with suspected dengue, although the study populations and
conclusions have differed [45-47]. Until these findings can be externally validated in a prospective fashion, the use of any of these algorithms in clinical practice cannot
be recommended.

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FUTURE DIRECTIONS Thus far, data do not support a role for corticosteroids [48-50], intravenous immunoglobulins, pentoxifylline, or activated factor VII [51-53].

Several approaches are under investigation for specific treatment of dengue, including direct viral inhibitors and modifiers of virus-host interactions [54,55]. Direct-acting
agents have included small molecule inhibitors of essential viral enzymes (NS2B-3 protease, NS3 helicase, NS5 methyltransferase, the NS5 polymerase) or small
molecule or antibody inhibitors of viral entry/fusion. A dengue mouse model has been validated and demonstrated to be a suitable test system for direct viral inhibitors
[56]. Several agents have demonstrated reduction of viremia and levels of proinflammatory cytokines in this model [57].

Randomized trials of chloroquine, lovastatin, balapiravir (a polymerase inhibitor), and celgosivir (an alpha-glucosidase inhibitor) among adults with dengue have not
noted a significant benefit on viremia, NS1 antigenemia, or fever [58-60].

INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. The Basics patient education
pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition.
These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer,
more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient
education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.)

Basics topic (see "Patient education: Dengue fever (The Basics)")

SUMMARY

Dengue is a febrile illness that is caused by one of four dengue virus types (DEN-1, DEN-2, DEN-3, and DEN-4). The likelihood for development of severe dengue
is highest among individuals who develop a second dengue infection caused by a different virus type from the first infection. Thus, severe disease occurs primarily
among individuals in areas where multiple serotypes circulate simultaneously. (See 'Introduction' above and 'Prevention' above.)

Approaches for prevention of dengue infection in endemic areas include mosquito control and vaccine development. Mosquito control is effective but is difficult to
sustain. The vaccine that is most advanced in development is CYD-TDV, a formulation of four chimeric yellow fever 17D-dengue vaccine viruses. It has been
licensed in a few endemic countries in Latin America and Southeast Asia but not the United States. (See 'Endemic areas' above.)

Most travelers from nonendemic countries are at low risk for severe dengue in the absence of prior dengue virus exposure; potential exceptions include frequent
international travelers, expatriates, frequently deploying military personnel, and immigrants from endemic areas returning to their countries of origin. (See
'Travelers' above.)

Patients with suspected dengue should be assessed carefully and directed to the appropriate care setting. Early recognition of severe disease and patients at
increased risk for severe disease are essential, with prompt initiation of more aggressive therapy when necessary. (See 'Phases of infection and clinical
assessment' above.)

Outpatient management is appropriate for patients with presumptive diagnosis of dengue in the absence of warning signs or coexisting condition (pregnancy,
infancy, old age, diabetes, renal failure, underlying hemolytic disease, obesity, or poor social situation). Patients should be instructed to take plenty of fluids and
watch for signs of dehydration. Inpatient management is warranted for patients with dengue and warning signs of severe infection, severe dengue infection, or
dengue infection with coexisting conditions. (See 'Outpatient management' above and 'Inpatient management' above.)

Patients warranting inpatient management should be assessed for signs of shock (table 1). In the absence of shock, patients may be managed as summarized in
the algorithm (algorithm 1). In the setting of shock (normal systolic pressure but rising diastolic pressure with narrowing pulse pressure), patients may be managed
as summarized in the algorithm (algorithm 2). In the setting of profound or prolonged shock, patients may be managed as summarized in the algorithm (algorithm
3). (See 'Management of plasma leakage' above and 'Treatment of shock' above.)

Fever and myalgias should be managed with acetaminophen; aspirin or nonsteroidal anti-inflammatory agents should be avoided. Gastrointestinal bleeding,
epistaxis, or menorrhagia may be severe enough to warrant blood transfusion. (See 'Management of fever' above and 'Management of bleeding' above.)

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Topic 3030 Version 26.0

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GRAPHICS

Dengue hemodynamic assessment

Prolonged/profound shock (DHF


Stable circulation Shock (DHF Grade III)*
Grade IV)*

Heart rate Normal Tachycardia Severe tachycardia or bradycardia

Blood pressure Normal Normal systolic pressure but rising diastolic Severe hypotension or undetectable blood
pressure (narrowing pulse pressure ) pressure
Postural hypotension

Respiratory rate Normal Tachypnea Hyperpnea or Kussmaul respirations

Urine output Normal Reducing trend Oliguria or anuria

Consciousness level Clear, lucid Clear, lucid Restless, combative

Capillary refill Brisk (2 seconds) Prolonged (>2 seconds) Very prolonged

Extremities Warm, pink Cool Cold, clammy, mottled skin

Peripheral pulse volume Good volume Weak, thready Feeble or absent

DHF: dengue hemorrhagic fever.


* The WHO has established the following grading system for severity of dengue hemorrhagic fever:
DHF Grade I Fever, hemorrhagic manifestation (positive tourniquet test), and evidence of plasma leakage.
DHF Grade II DHF Grade I plus spontaneous bleeding.
DHF Grade III DHF Grade I or DHF Grade II plus narrowing pulse pressure or hypotension.
DHF Grade IV DHF Grade III plus profound shock with undetectable blood pressure and pulse.
Dengue shock syndrome consists of DHF Grade III and DHF Grade IV.
Shock due to plasma leakage often presents with a narrow pulse pressure or elevated diastolic pressure with preserved systolic pressure, whereas shock due to bleeding often presents with
hypotension or low systolic pressure. Other causes of shock must also be considered (such as hypoglycemia, excessive vomiting, or bacterial coinfection).
Pulse pressure is systolic pressure minus diastolic pressure.

Modified from: Centers for Disease Control and Prevention. Dengue case management. Available at: http://www.cdc.gov/dengue/resources/dengue-clinician-guide_508.pdf (Accessed on
September 15, 2016).

Graphic 109848 Version 1.0

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An approach to inpatient management of dengue infection with plasma leakage in the absence of shock (WHO DHF Grades I and
II)*

WHO: World Health Organization; DHF: dengue hemorrhagic fever.


* The WHO has established a grading for severity of dengue hemorrhagic fever:
DHF Grade I Fever, hemorrhagic manifestation (positive tourniquet test), and evidence of plasma leakage.
DHF Grade II DHF Grade I plus spontaneous bleeding.
DHF Grade III DHF Grade I or DHF Grade II plus circulatory failure.
DHF Grade IV DHF Grade III plus profound shock with undetectable blood pressure and pulse.
Dengue shock syndrome consists of DHF Grade III and DHF Grade IV. Shock refers to normal systolic pressure but rising diastolic pressure with narrowing pulse pressure.
Inpatient management is warranted for high-risk patients (infants, pregnant women, older adults, obese, diabetes, renal failure, neurologic signs), patients with significant bleeding, patients
with leukopenia (white blood cell count 5000 cells/mcL), patients with thrombocytopenia (platelet count 10,000 cells/mcL), and patients with warning signs of severe dengue (as defined in Box
D above).
Criteria for clinical stability include blood pressure rising or normalized, heart rate decreasing, pulse pressure widening, respiratory rate decreasing, or skin warm with turgor intact.
Criteria for clinical instability include blood pressure decreasing, heart rate increasing, pulse pressure narrowing, respiratory rate increasing, or skin cool and clammy with diminished turgor.
No other colloid formulations (such as albumin) should be used for management of dengue. If 10% dextran 40 in normal saline is not available, crystalloid should be used.
The patient's clinical status (including vital signs, urine output, and hematocrit) should be evaluated prior to each infusion rate adjustment.

Data from:
1. World Health Organization. Comprehensive Guidelines for Prevention and Control of Dengue and Dengue Haemorrhagic Fever. WHO, New Delhi 2011.
2. World Health Organization. Dengue: Guidelines for diagnosis, treatment, prevention and control. WHO, Geneva 2009.

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An approach to management of dengue infection in the setting of shock, narrowed pulse pressure, or hypotension
(WHO DHF Grade III)*

WHO: World Health Organization; DHF: dengue hemorrhagic fever.


* The WHO has established a grading for severity of dengue hemorrhagic fever:
DHF Grade I Fever, hemorrhagic manifestation (positive tourniquet test), and evidence of plasma leakage.
DHF Grade II DHF Grade I plus spontaneous bleeding.
DHF Grade III DHF Grade I or DHF Grade II plus circulatory failure.
DHF Grade IV DHF Grade III plus profound shock with undetectable blood pressure and pulse.
Dengue shock syndrome consists of DHF Grade III and DHF Grade IV.
Shock refers to normal systolic pressure but rising diastolic pressure with narrowing pulse pressure. Profound shock refers to hypotension and narrow pulse pressure
(systolic minus diastolic pressure 20 mmHg).
Criteria for clinical improvement include blood pressure rising or normalized, heart rate decreasing, pulse pressure widening, respiratory rate decreasing, skin warm with
turgor intact, or sensorium clear.
Criteria for lack of clinical improvement include blood pressure decreasing, heart rate increasing, pulse pressure narrowing, respiratory rate increasing, skin cool and clammy
with diminished turgor, mental confusion, or restlessness.
No other colloid formulations (such as albumin) should be used for management of dengue. If 10% dextran 40 in normal saline is not available, crystalloid should be used.
The patient's clinical status (including vital signs, urine output, and hematocrit) should be evaluated prior to each infusion rate adjustment.

Data from:
1. World Health Organization. Comprehensive Guidelines for Prevention and Control of Dengue and Dengue Haemorrhagic Fever. WHO, New Delhi 2011.
2. World Health Organization. Dengue: Guidelines for diagnosis, treatment, prevention and control. WHO, Geneva 2009.

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An approach to management of dengue infection in the setting of profound or prolonged shock (WHO DHF
Grade IV)*

WHO: World Health Organization; DHF: dengue hemorrhagic fever.


* The WHO has established a grading for severity of dengue hemorrhagic fever
DHF Grade I Fever, hemorrhagic manifestation (positive tourniquet test), and evidence of plasma leakage.
DHF Grade II DHF Grade I plus spontaneous bleeding.
DHF Grade III DHF Grade I or DHF Grade II plus circulatory failure.
DHF Grade IV DHF Grade III plus profound shock with undetectable blood pressure and pulse.
Dengue shock syndrome consists of DHF Grade III and DHF Grade IV.
Shock refers to normal systolic pressure but rising diastolic pressure with narrowing pulse pressure. Profound shock refers to hypotension and narrow pulse
pressure (systolic minus diastolic pressure 20 mmHg).
Intravenous crystalloid solutions include normal saline or Ringer's lactate. Colloid solution includes blood products or 10% dextran 40 in normal saline; no
other colloid formulations (such as albumin) should be used for management of dengue, and dextran should not be used for initial resuscitation. If 10% dextran
40 in normal saline is not available, crystalloid should be used.
Criteria for clinical improvement include blood pressure rising or normalized, heart rate decreasing, pulse pressure widening, respiratory rate decreasing, skin
warm with turgor intact, or sensorium clear.
The patient's clinical status (including vital signs, urine output, and hematocrit) should be evaluated prior to each infusion rate adjustment.
Criteria for lack of clinical improvement include blood pressure decreasing, heart rate increasing, pulse pressure narrowing, respiratory rate increasing, skin
cool and clammy with diminished turgor, mental confusion, or restlessness.
Additional interventions include dialysis or plasmapheresis; the clinical approach depends on locally available resources and clinical expertise.

Data from:
1. World Health Organization. Comprehensive Guidelines for Prevention and Control of Dengue and Dengue Haemorrhagic Fever. WHO, New Delhi 2011.
2. World Health Organization. Dengue: Guidelines for diagnosis, treatment, prevention and control. WHO, Geneva 2009.

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